Pyrethroids are highly potent insecticides of increasing economic importance as replacement compounds in many areas of insect control. Pyrethroids act to compromise nerve impulse transmission, but structure-activity relationships in neurotoxicity do not correlate with structure-insecticidal activity relationships, and it is therefore uncertain whether observed neurophysiological phenomena in fact describe the mode of toxic action of pyrethroids. Prediction of the specificity of the site of action from overall structure-activity relationships is limited by the possible effects of selectivity in penetration, transport to the site of action, and metabolic detoxification and excretion in modifying intrinsic specificity. Therefore, in order to gain further knowledge of the mode and site of action of pyrethroids it is necessary to identify intrinsic structure-activity relationships at the site of action as well as those governing overall biological activity. The proposed research program will examine the effect of structural variation on the penetration, distribution, and metabolism of selected pyrethroids in insects. These studies will provide insight into the modifying effect of pharmacokinetics on intrinsic activity and will define the fundamental structure-activity relationships at the site of action. Further studies will employ these structure-intrinsic activity data in the investigation of specific pyrethroid binding in nervous tissue preparations from insects and mammals as a method of locating and characterizing the site of action of pyrethroids. These results will contribute significantly to the understanding of the highly specific interaction between pyrethroids and nervous system components and will aid the rational design of new safe and effective insecticides.